ELFABRIO Concentrate for solution for infusion Ref.[50956] Active ingredients: Pegunigalsidase alfa

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Infusion related reactions

Infusion-related reactions (IRRs), defined as any related adverse events with onset after start of infusion and up to 2 hours after end of infusion have been reported (see section 4.8). The most commonly observed symptoms of IRRs were hypersensitivity, itching, nausea, dizziness, chills and muscular pain.

The management of IRRs must be based on the severity of the reaction, and include slowing the infusion rate and treatment with medicinal products such as antihistamines, antipyretics and/or corticosteroids, for mild to moderate reactions. Pre-treatment with antihistamines and/or corticosteroids may prevent subsequent reactions in those cases where symptomatic treatment was required, although IRRs occurred in some patients after receiving pre-treatment (see section 4.2).

Hypersensitivity

Hypersensitivity reactions have been reported in patients in clinical studies (see section 4.8). As with any intravenous protein product, allergic-type hypersensitivity reactions may manifest and can include localised angioedema (including swelling of the face, mouth, and throat), bronchospasm, hypotension, generalised urticaria, dysphagia, rash, dyspnoea, flushing, chest discomfort, pruritus, and nasal congestion. If a severe allergic or anaphylactic-type reactions occur, immediate discontinuation of Elfabrio is recommended and current medical standards for emergency treatment are to be followed. In patients who have experienced severe hypersensitivity reactions during Elfabrio infusion, caution should be exercised upon re-challenge and appropriate medical support should be readily available. Moreover, for patients who experienced severe hypersensitivity reactions with ERT infusion including Elfabrio, appropriate medical support should be readily available.

Immunogenicity

In clinical studies, treatment-induced anti-drug antibodies (ADA) development has been observed (see section 4.8).

The presence of ADAs to Elfabrio may be associated with a higher risk of infusion-related reactions, and severe IRRs are more likely to occur in ADA positive patients. Patients who develop infusion or immune reactions with Elfabrio treatment should be monitored.

Additionally, patients who are ADA positive to other enzyme replacement therapies, who have experienced hypersensitivity reactions to Elfabrio and patients who are switching to Elfabrio should be monitored.

Glomerulonephritis membranoproliferative

Depositions of immune complexes can potentially occur during treatment with ERTs, as a manifestation of immunological response to the product. A single case of glomerulonephritis membranoproliferative was reported during the clinical development of Elfabrio, due to immune depositions in the kidney (see section 4.8). This event led to a temporary decline in renal function, which improved upon discontinuation of the medicinal product.

Excipients of known effect

This medicinal product contains 48 mg sodium per vial, equivalent to 2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

No interaction studies and no in vitro metabolism studies have been performed. Based on its metabolism, pegunigalsidase alfa is an unlikely candidate for cytochrome P450 mediated drug-drug interactions.

Elfabrio is a protein and is expected to be metabolically degraded through peptide hydrolysis.

Pregnancy

There are no or limited amount of data from the use of pegunigalsidase alfa in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Elfabrio during pregnancy unless clearly necessary.

Breast-feeding

It is unknown whether pegunigalsidase alfa/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of Elfabrio in milk (for details see section 5.3). A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Elfabrio therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There are no studies assessing the potential effect of pegunigalsidase alfa on fertility in humans. Animal studies show no evidence of impaired fertility (see section 5.3).

Dizziness or vertigo were observed in some patients following Elfabrio administration. These patients should refrain from driving or the use of machines until symptoms have subsided.

Summary of the safety profile

The most common adverse reactions were infusion-related reactions reported in 6.3% of patients, followed by hypersensitivity and asthenia reported each by 5.6% of patients.

In clinical studies, 5 patients (3.5%) experienced a serious reaction that was considered related to Elfabrio. Four of these reactions were confirmed IgE-mediated hypersensitivity (bronchospasm, hypersensitivity) that occurred at the first infusion of Elfabrio and resolved within the day after occurrence.

Tabulated summary of adverse reactions

The data described below reflects data from 141 patients with Fabry disease who received Elfabrio in 8 clinical studies, following the posology of 1 mg/kg every two weeks or 2 mg/kg every four weeks for a minimum of 1 infusion up to 6 years.

Adverse reactions are listed in Table 2. Information is presented by system organ class. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); frequency not known (cannot be estimated from available data).

Table 2. Adverse reactions reported during treatment with Elfabrio:

The following preferred terms have been grouped in Table 2:

• hypersensitivity includes: drug hypersensitivity
• agitation includes: nervousness
• abdominal pain includes: abdominal discomfort
• rash includes: rash maculo-papular and rash pruritic
• musculoskeletal stiffness recorded as musculoskeletal pain includes: myalgia
• asthenia includes: malaise and fatigue
• chest pain includes: chest discomfort and non-cardiac chest pain
• pain includes: pain in extremity
• oedema peripheral recorded as oedema

^* Preferred terms considered as IRR as described in the section below.

Description of selected adverse reactions

Infusion related reactions (adverse reactions within 2 hours of infusion)

IRRs were reported in a total of 32 patients (22%): 26 patients (23%) treated with 1 mg/kg every two weeks and 6 patients (20%) treated with 2 mg/kg every four weeks. The most commonly reported symptoms associated with IRRs reported for 1 mg/kg dosage were: hypersensitivity, chills, dizziness, rash and itching. For the 2 mg/kg dose the most commonly reported symptom was pain. IRRs were mostly mild or moderate in intensity and resolved with continuous treatment; however, 5 patients (all male, 1 mg/kg dose) experienced 5 severe IRRs. These 5 IRRs were also serious. Four of these events were confirmed type I hypersensitivity reactions and 3 led to the discontinuation from the study. Another patient was later withdrawn from the study, after the occurrence of another moderate IRR. All 5 patients however recovered within the day after of occurrence with appropriate treatment. IRRs predominantly occurred within the first year of treatment with Elfabrio and no serious IRR was observed during the second year and beyond.

Immunogenicity

In clinical studies, 17 out of 111 of patients (16%) treated with 1 mg/kg Elfabrio every two weeks and 0 out of 30 patients treated with 2 mg/kg Elfabrio every four weeks developed treatment-induced antidrug antibodies (ADAs).

Glomerulonephritis membranoproliferative

During the clinical development of Elfabrio, one patient out of 136 reported a severe event of glomerulonephritis membranoproliferative after receiving treatment for more than 2 years. The patient was ADA positive at the start of the infusions. The event led to a transitory reduction in the eGFR and an increase on the level of proteinuria, with no additional signs or symptoms. A biopsy revealed the immune-complex mediated nature of this event. Upon discontinuation of the treatment, the eGFR values stabilised and the glomerulonephritis was reported as resolving.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.